12-21438095-G-C

Position:

• chr12-21438095-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024854.5(PYROXD1):​c.84+281G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.02 in 429,496 control chromosomes in the GnomAD database, including 122 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (37 hom., cov: 33)
  • Exomes 𝑓: 0.020 (85 hom.)
• Consequence: PYROXD1 NM_024854.5 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.17

Genes affected

PYROXD1 (HGNC:26162): (pyridine nucleotide-disulphide oxidoreductase domain 1) This gene encodes a nuclear-cytoplasmic pyridine nucleotide-disulphide reductase (PNDR). PNDRs are flavoproteins that catalyze the pyridine nucleotide-dependent reduction of thiol residues in other proteins. The encoded protein belongs to the class I pyridine nucleotide-disulphide oxidoreductase family but lacks the C-terminal dimerization domain found in other family members and instead has a C-terminal nitrile reductase domain. It localizes to the nucleus and to striated sarcomeric compartments. Naturally occurring mutations in this gene cause early-onset myopathy with internalized nuclei and myofibrillar disorganization. A pseudogene of this gene has been defined on chromosome 11. [provided by RefSeq, Apr 2017]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 12-21438095-G-C is Benign according to our data. Variant chr12-21438095-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 1183822.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0201 (3055/152288) while in subpopulation AFR AF= 0.0247 (1027/41560). AF 95% confidence interval is 0.0235. There are 37 homozygotes in gnomad4. There are 1498 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 37 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PYROXD1	NM_024854.5	c.84+281G>C		intron_variant		ENST00000240651.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PYROXD1	ENST00000240651.14	c.84+281G>C		intron_variant		1	NM_024854.5	P1

Frequencies

GnomAD3 genomes AF: 0.0200 AC: 3038 AN: 152170 Hom.: 35 Cov.: 33

Gnomad AFR AF: 0.0244

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0141

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.0201

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0208

Gnomad OTH AF: 0.0225

GnomAD4 exome AF: 0.0200 AC: 5551 AN: 277208 Hom.: 85 Cov.: 0 AF XY: 0.0200 AC XY: 2867 AN XY: 143252

Gnomad4 AFR exome AF: 0.0244

Gnomad4 AMR exome AF: 0.0137

Gnomad4 ASJ exome AF: 0.0138

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0126

Gnomad4 FIN exome AF: 0.0187

Gnomad4 NFE exome AF: 0.0233

Gnomad4 OTH exome AF: 0.0219

GnomAD4 genome AF: 0.0201 AC: 3055 AN: 152288 Hom.: 37 Cov.: 33 AF XY: 0.0201 AC XY: 1498 AN XY: 74454

Gnomad4 AFR AF: 0.0247

Gnomad4 AMR AF: 0.0141

Gnomad4 ASJ AF: 0.0109

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0112

Gnomad4 FIN AF: 0.0201

Gnomad4 NFE AF: 0.0208

Gnomad4 OTH AF: 0.0223

Alfa AF: 0.0196 Hom.: 5

Bravo AF: 0.0203

Asia WGS AF: 0.00751 AC: 27 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.6
DANN	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs113058309; hg19: chr12-21591029;